The hypothalamic-pituitary adrenal (HPA) axis is a centrally controlled, stress-responsive neuroendocrine system. It plays a pathophysiological role in diseases as divergent as depression, breast cancer and AIDS, by linking psychosocial stressors to cognitive/emotional and physiological responses that can disrupt homeostatic regulation. Better understanding of how psychosocial factors modulate activity of the HPA axis will advance our understanding of how they accelerate and moderate the course of these diseases. Laboratory study of specific cognitive and emotional modulators could facilitate refinement and wider application of psychosocial interventions capable of ameliorating progression and burden of these diseases. It can also help identify the biological mechanism through which psychosocial factors modulate the HPA axis. The goals of this proposal are (1) to demonstrate that cognitive/emotional factors are in fact potent modulators of human HPA axis reactivity to pharmacological and psychological challenges and (2) to begin to identify the specific psychological factors that are most salient to the axis. The long-term objectives are (1) to use more precise identification of these factors to develop improved stress inoculation interventions and (2) to advance general and mechanistic understanding of the psychobiology of stress sensitivity and resilience. Specifically, the project will build on previously funded work demonstrating that a brief cognitive manipulation of expectancies, novelty, and perceived control significantly moderates the human HPA axis response to a robust pharmacological activator. This study will seek to replicate the impact of this cognitive intervention on the HPA axis, examine its potency with other pharmacological and psychological activators of the axis, and deconstruct the intervention to determine more precisely those cognitive/emotional components that are most impactful. Using a laboratory challenge paradigm and a random-assignment experimental design, the project will examine the effects of a brief cognitive intervention on adrenocorticotropin (ACTH) and cortisol response to a cholecystokinin-B receptor agonist (pentagastrin), to corticotropin-releasing hormone, and to the Trier Social Stress Test. Existing animal data will be used to identify factors within the cognitive intervention which likely account for its potency and dismantling studies will be done to examine the separable effects of these factors.